Targeted cancer therapy is designed to disrupt the function of specific molecules needed for carcinogenesis and tumor growth and thus either kills or prevents the growth of cancer cells (Ji H et al (2006) Cell Cycle 5(18):2072-2076 Epub 2006 Sep. 15). In contrast to conventional cytotoxic chemotherapy, such targeted cancer therapies may be more effective and less harmful to normal cells. A main effort in the targeted cancer therapy field has been the development of agents that target the epidermal growth factor receptor (EGFR). EGFR is a member of the ErbB family of closely related receptors including EGFR (ErbB-1), Her2/neu (ErbB-2), Her3 (ErbB-3) and Her4 (ErbB-4). Activation of EGFR leads to receptor tyrosine kinase activation and a series of downstream signaling events that mediate cellular proliferation, motility, adhesion, invasion, and resistance to chemotherapy as well as inhibition of apoptosis (2-4), processes that are crucial to the continual proliferation and survival of cancer cells.
To date, two major types of anti-EGFR agents have entered the clinical setting: anti-EGFR antibodies and small molecule EGFR tyrosine kinase inhibitors(TKIs) (5, 6). Anti-EGFR antibodies such as cetuximab were designed to bind to the extra-cellular domain of the EGFR and block activation of EGFR downstream signaling (7). Cetuximab (also known as antibody 225, U.S. Pat. No. 4,943,533) was raised against A431 cells, which express high levels of wild type EGFR. In contrast, small molecule TKIs such as gefitinib (compound ZD1839, Iressa) or erlotinib (compound OSI-774, Tarceva) compete with ATP for binding to the intracellular catalytic domain of the EGFR tyrosine kinase and, thus, prevent EGFR autophosphorylation and downstream signaling(4).
Both of these anti-EGFR drug groups have shown some clinical efficacy in a subset of patients with a variety of different types of cancers. Treatment with gefitinib or erlotinib in patients with lung cancer having EGFR kinase domain mutations often generate dramatic clinical responses (5, 8). However, the effectiveness of gefitinib or erlotinib in lung adenocarcinoma with wild type EGFR or in other histological subtype, such as squamous cell carcinoma is limited (9, 10). Furthermore, it has been shown in pre-clinical and clinical trials that gefitinib or erlotinib are largely ineffective in inhibiting the function of the EGFRvIII mutant (11), a distinct activating EGFR mutation in which there is an in-frame deletion of exon II to VII (also denoted EGFR de2-7). EGFRvIII is commonly found in glioblastomas and recently found to be present in a subset of human lung squamous cell carcinomas (12) and a large fraction of head and neck cancers (13).
Cetuximab is shown to be effective in a small subset of non-small cell lung cancer (NSCLC) patients, and patients with head and neck cancers, as well as colorectal cancer patients. However, the response to cetuximab does not seem to correlate with expression levels of EGFR. Thus, it is unclear why these patients respond while other cancer patients whose tumors have high EGFR expression are refractory to cetuximab treatment (14).
As expression of the EGFR vIII mutant receptor is restricted to tumor cells, it represents a highly specific target for antibody therapy. Accordingly, both polyclonal and monoclonal antibodies specific to the unique peptide of de2-7 EGFR have been generated. A series of mouse mAbs, isolated following immunization with the unique de2-7 peptide, all showed selectivity and specificity for the truncated receptor and targeted de2-7 EGFR positive xenografts grown in nude mice (Wikstrand C J et al (1995) Cancer Res 55:3140-3148; Okamoto, S et al (1996) Br J Cancer 73:1366-1372; Hills D et al (1995) Int J Cancer 63:537-543; Reist C J et al (1997) Cancer Res 57:1510-1515; Reist C J et al (1995) Cancer Res 55:4375-4382; U.S. Pat. No. 5,401,828). Examples of anti-EGFR viii antibodies include ABX-EGF (panitumumab), DH8.3, L8A.4, and Y10.
MAb806 is a novel murine antibody, originally raised to recognize the unique truncation mutant, EGFRvIII using whole cells expressing EGFR vIII mutant as immunogen (15-17). Importantly, the epitope recognized by mAb806 is not accessible in inactive wild-type (wt) EGFR, but is exposed in a transitional form of wt EGFR in cells with overexpression of EGFR, and expression of EGFRvIII (18). The epitope studies are supported by immunohistochemical studies demonstrating that the 806 antibody binds to epitopes present in gliomas, as well as a broad range of epithelial cancers, but not to normal human tissues (16, 19). These and other preclinical data suggest that mAb806 might have a different spectrum of clinical activity and side effect profile distinct from cetuximab and other anti-EGFR antibodies. In xenograft models, mAb806 has exhibited a potent anti-tumor activity with no targeting of normal tissues. Thus, the unique targeting capabilities of mAb806 represent a new paradigm for cancer-specific molecularly targeted therapy.
When overexpressed or activated by mutations, tyrosine kinases including EGFR contribute to the development of cancer and these mutated tyrosine kinase (TK) enzymes often provide a target or sensitivity for selective and specific cancer therapy. Somatic mutations in the tyrosine kinase domains of the EGFR gene are associated with sensitivity of lung cancers to certain tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib. In frame EGFR deletions in exon 19 (del L747-S752) and frequent point mutations in codon 858 (exon 21) (L858R) have been identified in non-small cell lung cancers and adenocarcinomas and associated with sensitivity to the TKIs gefitinib and erlotinib (Lynch T J et al (2004) N Engl J Med 350:2129-2139; Paez J G et al (2004) Science 304:1497-1500; Pao Wet at (2004) PNAS 101(36):13306-13311). Recent studies have shown that 10-30% of NSCLC patients have EGFR kinase domain mutations while 5% of lung squamous cell carcinoma (SCC) patients have the extracellular domain EGFRvIII mutation (12, 20). Methods to determine the responsiveness of cancer to EGFR targeting treatments, based on assessment of mutations in EGFR, particularly in the kinase domain, and predicted inhibitor sensitivity in patients are described in Bell et al (WO 2005/094357 and US20060147959).
Acquired resistance to chemotherapy or targeted cancer therapy, mediated by secondary resistance or compensatory mutations is an ongoing challenge. Tumors that are sensitive to TKIs, including either gefitinib or erlotinib, eventually progress despite continued treatment with the TKIs. A secondary mutation at position 790 of EGFR (T790M) has been identified in tumor biopsy of relapsed and resistant patients (Kobayashi S et al (2005) N Engl J Med 352(8):786-792). This mutation is predicted to lead to steric hindrance of inhibitor binding in the ATP-kinase-binding pocket.
In view of the existence and prevalence of acquired resistance to TKIs in EGFR mediated disease and the significant cancer relapse rate, there is a clinical need for more broadly effective treatment protocols, employing EGFR targeted agents which are effective against, target, or avoid acquired resistance in EGFR mutants and EGFR mediated disease.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.